Process for the manufacture and use of pancreatin micropellet cores

ABSTRACT

A process for manufacturing and using pancreatin micropellet cores and pancreatin micropellets which are substantially free of synthetic oils. In one embodiment, a pharmaceutical composition is provided comprising a pancreatin micropellet with the enteric coating being designed to deliver pancreatin to the upper portion of the intestine of a mammal for release.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.60/708,526 and 60/708,692 which were both filed Aug. 15, 2005 and areboth hereby incorporated by reference.

FIELD OF THE INVENTION

A process for the manufacture and use of a medicament containingpancreatin is described herein. More specifically, processes formanufacturing pancreatin micropellet cores which are substantially freeof synthetic oils are described. Also described herein are pancreatinmicropellets which are enteric-coated pancreatin micropellet cores.

BACKGROUND

Pancreatin microspheres are the treatment of choice for diseases ordisorders caused by digestive enzyme deficiency in mammals such ashumans. This is due to the fact that high-performance pancreatinmicrosphere products like Creon™ provide a therapeutically effectiveload of active enzymes while at the same time providing properly sizedmicrospheres capable of targeting the optimal location in the digestivetract where digestive enzyme activity will be needed, in particular theupper intestine.

Recently, governmental health authorities have initiated a reassessmentof the compatibility of certain pharmaceutical excipients which hadpreviously been used in the formulation of pancreatin-containingproducts and have provided advice concerning specific pharmaceuticalexcipients (see e.g. US Code of Federal Regulations, 21 CFR §201.302),such as mineral oil. It is recommended today that mineral oil not beprovided indiscriminately to either pregnant women or infants. Thus,there is a need provide patients with a pancreatin micropellet productin compliance with the current advice of the health authorities andwhich does not include synthetic oils such as mineral oil.

The use of synthetic oils like paraffins, e.g. liquid paraffins (mineraloils), in particular highly liquid paraffin (light mineral oil) haspreviously been understood to be a necessary excipient for manufacturingpancreatin micropellet products by extrusion and subsequentspheronisation of the extrudates. One example is described in documentEP 0 583 726 (U.S. Pat. No. 5,378,462), which discloses pancreatinmicropellets and their preparation with polyethylene glycol 4000,paraffin and a lower alcohol, by extrusion and subsequentspheronisation.

United States Pat. App. No. 2004/0101562 (Maio) discloses microspheresof pancreatic enzymes with high stability and a production methodthereof. A solid mixture, including one or more pancreatic enzymes, oneor more hydrophilic low-melting polymers and other excipients, is heatedat a temperature equal or higher than the melting temperature of saidhydrophilic low-melting polymer while stirring. However, Maio emphasizesthat a fundamental feature of the process described therein is the totalabsence of any solvents, either water or other organic solvents.

In United States Pat. App. No. 2002/0061302 a method for the treatmentof diabetes by administering a physiologically acceptable enzyme mixturehaving lipolytic, proteolytic and amylolytic activity to a patient inneed thereof is described.

US patent application No. 2004/0213847 relates to delayed pharmaceuticalcompositions containing proton pump inhibitors.

U.S. Pat. No. 4,786,505 teaches pharmaceutical preparations for oraluse.

Further pharmaceutical preparations which may comprise pancreatin and anenteric coating are e.g. known from documents DE 19907764; EP 0 021 129(U.S. Pat. No. 4,280,971); EP 0 035 780; U.S. Pat. Nos. 5,225,202;5,750,148; 6,224,910; U.S. Pat. App. No. 2002/0146451 or WO 02/40045.

SUMMARY

Accordingly, one embodiment disclosed herein is a process for making andusing pancreatin micropellet cores which are substantially free ofsynthetic oils. Another embodiment provides pancreatin micropelletssubstantially free of synthetic oils which are enteric-coated pancreatinmicropellet cores.

Another embodiment provides a method of treating various medicalconditions such as pancreatic exocrine insufficiency, pancreatitis,cystic fibrosis, diabetes type I and diabetes type II by using thepancreatin micropellet cores and/or pancreatin micropellets obtained bythe processes described herein.

Another embodiment provides a pharmaceutical composition in an oraldosage form containing a pharmacologically effective amount ofpancreatin wherein the pancreatin is in the form of pancreatinmicropellet cores and/or pancreatin micropellets manufactured accordingto the processes described herein.

Other objects, features and advantages will be set forth in the detaileddescription of the embodiments that follows, and in part will beapparent from the description or may be learned by practice of theclaimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof.

DETAILED DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit theinvention to the specific embodiments illustrated. The headings usedthroughout this disclosure are provided for convenience only and are notto be construed to limit the invention in any way. Embodimentsillustrated under any heading may be combined with embodimentsillustrated under any other heading.

Pancreatin is a mixture of different physiologically active endogenousingredients which are derived from mammalian pancreas glands andcomprised of several different digestive enzymes such as lipases,amylases and proteases. Mammalian pancreatic lipase is a valuabledigestive enzyme supplement for the treatment of various medicalconditions such as pancreatic exocrine insufficiency. However,pancreatic proteases and amylases also contribute to the therapeuticvalue of pancreatin. Pancreatin for pharmaceutical use is typically ofbovine or porcine origin with porcine pancreatin being preferred.

It has now been surprisingly found that pancreatin micropellet coreswhich are suitable for enteric coating, are high in enzymatic activityand are substantially free of synthetic oils like paraffins, e.g. highlyliquid paraffin, can be produced by the processes described herein. Ithas further been found that the manufacturing process described hereinis an improvement when compared to known processes which use mineral oilor known processes which would e.g. need more process steps to producepancreatin micropellet cores.

In particular, pancreatin micropellet cores can be produced by theprocess described herein which comprise about 10% to about 95% by weightof pancreatin, about 5% to about 90% by weight of at least onepharmaceutically acceptable binding agent and 0% to about 10% by weightof at least one pharmaceutically acceptable excipient. Morespecifically, pancreatin micropellet cores can be produced by theprocess described herein which comprise about 70% to about 90% by weightof pancreatin, about 10% to about 30% by weight of at least onepharmaceutically acceptable binding agent and 0% to about 5% by weightof at least one pharmaceutically acceptable excipient. In oneembodiment, pancreatin micropellet cores can be produced which compriseabout 70% to about 90% by weight pancreatin, and about 10% to about 30%by weight of at least one pharmaceutically acceptable binding agent.

For the purposes of the present disclosure, the prefix “micro” used todescribe a micropellet or a microsphere means that the diameter or eachof the individual dimensions (length, height, width) is equal to or lessthan about 5 mm. Producing pancreatin micropellet cores which areapproximately spherical and have a diameter of 0.5 to 2.0 mm ispreferred.

The term “synthetic oils” means unsaponifiable hydrocarbons or mixturesof hydrocarbons and comprises e.g. liquid and solid paraffins, inparticular liquid paraffins (mineral oils), more particularly highlyliquid paraffin (light mineral oil).

The phrase “substantially free of synthetic oils” means that themanufacturing processes described herein and used to make the pancreatinmicropellet cores and/or pancreatin micropellets do not utilize one ormore synthetic oils as an excipient although synthetic oils may bepresent as pharmaceutically acceptable trace contaminants in thepancreatin, binding agent(s), enteric coating constituents, theenzyme-friendly organic solvents and/or excipients which are used tomanufacture the pancreatin micropellet cores and/or pancreatinmicropellets described herein.

One embodiment described herein is a process for the manufacture ofpancreatin micropellet cores, comprising the steps of:

-   a. preparing an extrudable mixture comprising:    -   i. about 10% to about 95% pancreatin;    -   ii. about 5% to about 90% of at least one pharmaceutically        acceptable binding agent;    -   iii. 0% to about 10% of at least one pharmaceutically acceptable        excipient; and    -   iv. one or more enzyme-friendly organic solvents in an amount        sufficient to form an extrudable mixture; wherein the        percentages of components are weight to weight of the pancreatin        micropellet cores;-   b. creating pancreatin micropellet cores from the extrudable    mixture;-   c. forming the pancreatin micropellet cores into approximately    spherical or approximately ellipsoidal shape in the presence of    additional enzyme-friendly organic solvent; and-   d. removing the one or more enzyme-friendly organic solvents from    the pancreatin micropellet cores such that the pancreatin    micropellet cores are substantially free of the one or more    enzyme-friendly organic solvents;

wherein the pancreatin micropellet cores are substantially free ofsynthetic oils.

Examples of pharmaceutically acceptable binding agents includepolyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethyleneglycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose,polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen andmixtures of said organic polymers. The foregoing list ofpharmaceutically acceptable binding agents is not meant to beexhaustive, but merely illustrative as a person or ordinary skill in theart would understand that many other pharmaceutically acceptable bindingagents or combination of binding agents could also be used. Polyethyleneglycol 4000 is the preferred pharmaceutically acceptable binding agent.For the purposes of the present disclosure, synthetic oils are not to beregarded as suitable pharmaceutically acceptable binding agents.

Examples of suitable pharmaceutically acceptable excipients includegliding agents like magnesium stearate or calcium stearate, stearicacid, talcum and/or starch; fillers like calcium phosphate, corn starch,dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose,kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calciumcarbonate, sorbitol and/or talcum; disintegrating agents like Aerosil™(silicic acid), alginic acid, amylose, calcium alginate, calciumcarbonate, formaldehyde gelatin, pectic carbonate, sago starch, sodiumbicarbonate and/or starch; and/or moisturizers like glycerol and/orstarch. The foregoing list of pharmaceutically acceptable excipients isnot meant to be exhaustive, but merely illustrative as a person orordinary skill in the art would understand that many otherpharmaceutically acceptable excipients or combination of excipientscould also be used. For the purposes of the present disclosure,synthetic oils are not to be regarded as suitable pharmaceuticallyacceptable excipients. In one embodiment, the pancreatin micropelletcores contain no pharmaceutically acceptable excipients but canoptionally contain a higher load or dose of pancreatin.

Process variations wherein the pharmaceutically acceptable excipientsare present in an amount of 0% are preferred.

Enzyme-friendly organic solvents facilitate mixing and other processingprocedures and may afterwards be removed, for example, by drying.Typically, after removal of the enzyme-friendly organic solvents, acertain amount of solvent remains in the pancreatin micropellet cores.The remaining solvent in the micropellet cores can compriseenzymefriendly organic solvents, water, or a mixture of enzyme-friendlyorganic solvents with water. If water is present as a solvent, this willtypically have been present in the pancreatin which was used as thestarting material. The amount of solvent present in the pancreatinmicropellet cores after removal of the enzyme-friendly organic solventsis typically less than about 5% and normally less than about 3% byweight of the pancreatin micropellet core.

Examples of suitable enzyme-friendly organic solvents are acetone,chloroform, dichloromethane or straight-chained or branchedC₁₋₄-alcohols, particularly methanol, ethanol, 1-propanol, 2-propanol,2-butanol, tert-butanol or mixtures of said solvents. 2-propanol is thepreferred enzyme-friendly organic solvent. For the purposes of thepresent disclosure, synthetic oils are not to be regarded as suitableenzyme-friendly organic solvents. The enzyme-friendly organic solvent istypically used in an amount of about 15% to about 35% by weight,preferably of about 20% to about 30% by weight, relative to the amountof pancreatin used. The foregoing list of suitable enzyme-friendlyorganic solvents is not meant to be exhaustive, but merely illustrativeas a person or ordinary skill in the art would understand that manyother enzyme-friendly organic solvents or combination of solvents couldalso be used.

The amounts of pancreatin, pharmaceutically acceptable binding agent(s),pharmaceutically acceptable excipient(s) and/or enzyme-friendly organicsolvent may be varied by those skilled in the art to arrive at thepancreatin micropellet cores having the preferred composition andcharacteristics as indicated herein.

The term “substantially free of enzyme-friendly organic solvents” meansthat the quantity of enzyme-friendly organic solvents present in thepancreatin micropellet cores would be less than about 5% by weight ofthe pancreatin micropellet core.

Removal of the one or more enzyme-friendly organic solvents from thepancreatin micropellet cores in process step d.) means that saidpancreatin micropellet cores are subject to conditions whereby themicropellet cores become substantially free from enzyme-friendly organicsolvents. Removal of the enzyme-friendly organic solvents can be by anymethod known to those of ordinary skill in the art. The preferred methodis by drying. Additionally, removal of the one or more enzyme-friendlyorganic solvents would also typically result in the pancreatinmicropellet cores containing an amount of water which is less than about5% and typically less than about 3% by weight of the pancreatinmicropellet core.

In one embodiment, the pancreatin micropellet cores are created inprocess step b.) by extrusion. Remarkably, an extrudable mixture isobtained even though the mixture is substantially free of syntheticoils. In process step b.), if the creating of the micropellet cores fromthe extrudable mixture is accomplished by means of extrusion, then thetemperature preferably does not exceed about 70° C. during extrusion,more preferably the temperature does not exceed about 50° C. Also, inthe event of extrusion, piercing dies are preferably used which have ahole diameter of about 0.5 mm to about 2.0 mm, preferably of about 0.7mm to about 1.5 mm, e.g. 0.8 mm. If the extrudable mixture is extruded,then the extrudate fragments are brought to a suitable length for theforming step. This can be done e.g. by means of a cutting devicearranged downstream to the extruding press in a manner known to the aperson of ordinary skill in the art. The forming in process step c.) canbe carried out e.g. in a customary rounding apparatus. In the roundingapparatus, the extrudate fragments are then formed into an approximatelyspherical or approximately ellipsoidal shape in the presence ofadditional enzyme-friendly organic solvent which may be the same ordifferent than the enzyme-friendly organic solvent used in process stepa).

When prepared as described herein (substantially free of syntheticoils), processing of the extrudate fragments in the rounding apparatusis improved relative to other known processes. For example, a loweramount of enzyme-friendly organic solvent needs to be added when formingthe pancreatin micropellet cores into an approximately spherical orapproximately ellipsoidal shape and fewer of the extrudate fragmentsstick to parts of the rounding apparatus when the process is practicedwith an extruder and rounding apparatus.

A further embodiment comprises pancreatin micropellets which areenteric-coated pancreatin micropellet cores. For enteric coating, anyenteric coating can be used which is suitable for delivery of thepancreatin micropellet cores to the upper intestine and compatible withthe pancreatin micropellet cores. Examples are enteric coatings knownfrom U.S. Pat. No. 5,378,462 or commercially available enteric coatingslike Eudragit™ polymers. Preferred enteric coatings are ones that wouldnot require the presence of synthetic oils.

It has been found that the pancreatin micropellet cores and thepancreatin micropellets produced according to the processes disclosedherein and not using synthetic oils unexpectedly show essentially thesame properties as pancreatin micropellet cores and pancreatinmicropellets produced according to known processes using mineral oilsuch as the processes disclosed in U.S. Pat. No. 5,378,462. Inparticular, the pancreatin micropellet cores and the pancreatinmicropellets produced without using synthetic oils have a similarparticle size distribution, bulk density and are obtained in similaryields as the pancreatin micropellet cores and pancreatin micropelletsproduced according to processes which use synthetic oils. Further, thepancreatin micropellet cores produced without using synthetic oils, whencompared to similar pancreatin micropellets using synthetic oils, showsimilar appearances in their surface structures and a similarperformance when coated with an enteric coating to give pancreatinmicropellets.

In another embodiment, the enteric coating on the pancreatin micropelletcores comprises:

i) at least one film-forming agent;

ii) at least one plasticizer; and

iii) optionally at least one anti-sticking agent.

In one embodiment the enteric coating comprises between about 20% andabout 30% by weight, more preferably between about 22% and about 26% byweight, yet more preferably between about 22.5% and about 25% by weightof the total composition of the pancreatin micropellet.

Film-forming agent(s), plasticizer(s) and anti-sticking agent(s) (whenpresent) as used for preparing the enteric coating are hereinaftercommonly referred to as “non-solvent coating constituents”.

Suitable film-forming agents include agar, Carbopol™ (carbomer) polymers(i.e. high molecular weight, crosslinked, acrylic acid-based polymers),carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen,cellulose acetate phthalate, cellulose acetate succinate, celluloseacetate trimelliate, chitin, corn protein extract, ethyl cellulose, gumarabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methacrylic acid-ethylmethacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetatephthalate, polivinyl alcohol, shellac, sodium alginate, starch acetatephthalate and/or styrene/maleic acid copolymer or mixtures of saidfilm-forming polymers. Cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate and/or methacrylic acid-ethylmethacrylate-copolymer are the preferred film-forming agents. Mostpreferred is hydroxypropyl methylcellulose phthalate, e.g. HP 55 orHPMCP HP-50. Synthetic oils are not to be regarded as preferredfilm-forming agents. The foregoing list of film-forming agents is notmeant to be exhaustive but merely illustrative, as a person or ordinaryskill in the art would understand that many other film-forming agents orcombination of film-forming agents could also be used.

The plasticizer(s) may generally be present in an amount greater thanabout 1.5%, and typically in an amount of about 2% to about 20% byweight, relative to the film-forming agent. The plasticizer may containsaturated linear monohydric alcohols having 12 to 30 carbon atoms. Morespecifically, acceptable plasticizers include lauryl alcohol, tridecylalcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecylalcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenylalcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissylalcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid esters ofglycerol, glycerol, polyethylene glycol, propyleneglycol, sorbitan fattyacids, triacetin, triethyl citrate and mixtures of said plasticizers.Preferred plasticizers are cetyl alcohol, stearyl alcohol, triethylcitrate and mixtures thereof. When cetyl alcohol is used as a singleplasticizer, it may be present in an amount of greater than about 1.5%,typically in an amount of about 2% to about 15%, preferably about 2% toabout 10%, by weight relative to the film-forming agent. When triethylcitrate is used as a single plasticizer, it may be present in an amountof about 5% to about 20%, preferably about 12% to about 15%, by weightrelative to the film-forming agent. Synthetic oils are not to beregarded as preferred plasticizers. The foregoing list of plasticizersis not meant to be exhaustive but merely illustrative, as a person orordinary skill in the art would understand that many other plasticizersor combination of plasticizers could also be used.

In one embodiment the plasticizer is comprised of cetyl alcohol andtriethyl citrate which are collectively present in an amount of greaterthan about 3%, typically in an amount of about 4% to about 20%, inparticular between about 6% and about 15%, more particularly betweenabout 7% and about 10%, by weight in relation to the film-forming agent.When the plasticizer is comprised of both cetyl alcohol and triethylcitrate, the weight to weight ratio of cetyl alcohol to triethyl citratemay be from about 0.05:1 to about 1:1, for example 0.1:1, 0.2:1, 0.3:1,0.4:1, 0.5:1, 0.6:1, 0,7:1, 0.8:1 or 0.9:1. In particular, the ratio ofcetyl alcohol to triethyl citrate in said mixture of cetyl alcohol andtriethyl citrate may be from about 0.25:1 to about 0.5:1, preferablyfrom about 0.3:1 to about 0.45:1, more preferably from about 0.35:1 toabout 0.4:1, and even more preferably from about 0.38:1 to about 0.4:1(w/w).

The enteric coating optionally comprises an anti-sticking agent.Suitable anti-sticking agents include dimethicone and castor oil.Dimethicone, in particular dimethicone 1000, is the preferredanti-sticking agent. The amount of anti-sticking agent (if present) inthe enteric coating is between about 1.5% and about 3% by weightrelative to the film-forming agent. Synthetic oils are not to beregarded as preferred anti-sticking agents. The foregoing list ofanti-sticking agents is not meant to be exhaustive but merelyillustrative, as a person or ordinary skill in the art would understandthat many other anti-sticking agents or combination of anti-stickingagents could also be used.

Additional embodiments are also located in U.S. Pat. App. No. ______filed on Aug. 15, 2006 and claiming the benefit of U.S. ProvisionalApplication Nos. 60/708,526 and 60/708,692 which were both filed onAugust 15, 2005. U.S. Pat. App. No. ______ is hereby incorporated byreference.

Another embodiment provides a process for the manufacture of pancreatinmicropellets, comprising the steps of:

-   aa. providing pancreatin micropellet cores wherein the pancreatin    micropellet cores are substantially free of synthetic oils;-   bb. providing an enteric-coating solution comprising    -   i. one or more film-forming agents;    -   ii. a plasticizer in an amount greater than about 1.5% by weight        relative to the one or more film-forming agents; and    -   iii. optionally, at least one anti-sticking agent, and    -   iv. one or more enzyme-friendly organic solvent(s);-   cc. coating the pancreatin micropellet cores with the    enteric-coating solution wherein the temperature of the pancreatin    micropellet cores during coating is kept at a temperature suitable    for applying the enteric-coating solution; and-   dd. drying the coated pancreatin micropellet cores.

In the foregoing process for producing pancreatin micropellets, thefilm-forming agent(s), the plasticizer(s), the anti-sticking agent(s)and the enzyme-friendly organic solvents generally have the meanings aspreviously set forth.

Due to the process for producing pancreatin micropellets, viz thecoating process as described herein, pharmaceutically acceptableresidual amounts of the enzyme-friendly organic solvent(s) present inthe enteric-coating solution may still be present in the pancreatinmicropellet after drying. It is understood that pancreatin micropelletscomprising pharmaceutically acceptable residual amounts ofenzyme-friendly organic solvent(s) are within the scope of the presentinvention.

Process step bb) may be performed at a temperature between about 15° C.and about 60° C. Performing process step bb) at ambient temperature (Le.room temperature, approximately between about 20° C. and about 30° C.),is preferred. Examples of suitable enzyme-friendly organic solventsinclude acetone, 2-butanol, tert.-butanol, chloroform, dichloromethane,ethanol, methanol, 1-propanol, 2-propanol and mixtures of said solvents.Acetone, ethanol and 2-propanol or their mixtures are preferred asenzyme-friendly organic solvents. Acetone is most preferred. Theforegoing list of enzyme-friendly organic solvents in process step bb.)is not meant to be exhaustive but merely illustrative, as a person orordinary skill in the art would understand that many otherenzyme-friendly organic solvents or combination of solvents could alsobe used.

The enzyme-friendly organic solvent is typically used in an amountbetween about 6 and about 10 times, preferably between about 7 and about8 times, the weight of the non-solvent coating constituents used toprepare the pancreatin micropellets. For example, if the non-solventcoating constituents make up to a total weight of about 1.5 g, thenabout 9 g to about 15 g of enzyme-friendly organic solvent may be usedin process step aa).

In process step cc.) the product temperature of the pancreatinmicropellet cores, in one embodiment, is usually maintained betweenabout 30° C. and about 60° C. while coating, preferably between about32° C. and about 55° C., more preferred between about 35° C. and about50° C., most preferably between about 37° C. and about 49° C. In processstep cc.), when cetyl alcohol or a mixture of cetyl alcohol and triethylcitrate is used the product temperature of the pancreatin micropelletcores is maintained between about 40° C. and about 46° C. Maintainingthe product temperature of the pancreatin micropellet cores within thepreferred temperature ranges while coating results in improvedgastric-acid resistant properties of the pancreatin micropellets, inparticular when the enteric coating comprise cetyl alcohol and triethylcitrate as plasticizers. The coating in process step cc.) can beaccomplished by any process or method known to a person of ordinaryskill in the art. Spray coating is preferred. Usually, process step cc.)is performed in a way that the enteric coating comprises between about20% and about 30% by weight, preferably between about 22% and about 26%by weight and more preferably between about 22.5% and about 25% byweight of the total composition of the pancreatin micropellet. The exactparameters to be applied in process step cc.) to achieve the desiredenteric coating will depend on the coating technique used. The personskilled in the art understands how to achieve coating films of a desiredthickness when using different coating techniques.

Drying of the enteric-coated pancreatin micropellet cores in processstep dd.) is performed between about 30° C. and about 75° C. preferablybetween about 30° C. and about 55° C., preferably between about 35° C.and about 50° C., and for a period of between about 6 hours and about 60hours, preferably for a period of between about 10 hours and about 36hours.

Pancreatin micropellets according to the invention are particularlysuitable for delivery of pancreatin and its digestive enzymeconstituents to the upper intestine, in particular to the smallintestine, usually to the duodenum, of mammals such as humans. Thus,pancreatin micropellets according to the invention are useful for theprophylaxis and/or treatment of various medical conditions and digestivedisorders including pancreatic exocrine insufficiency of differentorigins like maldigestion, and/or for the prophylaxis and/or treatmentof pancreatitis, cystic fibrosis, diabetes type 1 and/or diabetes typeII in mammals such as humans. Maldigestion in mammals such as humans isusually based on a deficiency of digestive enzymes, in particular on adeficiency of endogenous lipase, but also of protease and/or amylase.The cause of such a deficiency of digestive enzymes is frequently ahypofunction of the pancreas (e.g. pancreatic insufficiency, usuallyknown as pancreatic exocrine insufficiency), the organ which producesthe largest quantity of, and the most important, endogenous digestiveenzymes. If the pancreatic insufficiency is pathological, it may becongenital or acquired. Acquired chronic pancreatic insufficiency may,for example, result from alcoholism. Congenital pancreatic insufficiencymay, for example, result from disease such as cystic fibrosis. Theconsequences of the deficiency of digestive enzymes may be severesymptoms of under-nutrition and malnutrition, which may be accompaniedby increased susceptibility to secondary illnesses. In one specificembodiment, pancreatin micropellets according to the invention aretherefore particularly suited for treating pancreatic exocrineinsufficiency of any origin.

In another embodiment, pancreatin micropellets are provided aspreviously described, for the manufacture of a medicament for thetreatment of medical conditions such as digestive disorders, pancreaticexocrine insufficiency, pancreatitis, cystic fibrosis, diabetes type Iand/or diabetes type II.

In yet another embodiment, a method is provided for the treatment of amedical condition such as digestive disorders, pancreatic exocrineinsufficiency, pancreatitis, cystic fibrosis, diabetes type I and/ordiabetes type II by administering a therapeutically effective amount ofpancreatin micropellets previously described to a mammalian subject inneed of such treatment.

A further embodiment includes a pharmaceutical composition comprising apharmacologically effective amount of pancreatin wherein the pancreatinis in the form of pancreatin micropellets manufactured according to theprocesses described herein in a dosage form suitable for oraladministration containing said pharmacologically effective amount ofpancreatin. The pancreatin micropellets described herein maybe placedinto pharmaceutically acceptable dosages forms such as capsules orsachets. Capsules or sachets maybe opened to permit mixing of thecontents with compatible foods or liquids to facilitate administrationof the contents of the capsule or sachet.

For proper delivery of an acid-labile drug like pancreatin to the upperintestine of a mammal such as a human, it is necessary that an entericcoating be gastric acid resistant up to a pH of about 5.5. Subsequently,the acid-labile drug will need to be released to the upper intestinewhich means that the enteric coating must release the acid-labile drugin a less acidic environment, e.g. at about pH 5.5 or higher, inparticular at a pH of about 6. The pancreatin micropellets describedherein possess superior gastric acid resisting and protectiveproperties, e.g. superior protective properties at about pH 1 and/orabout pH 5. Pancreatin micropellets according to the invention whereinthe plasticizer is a mixture of cetyl alcohol and triethyl citrate asdescribed above (“CA/TEC-Compositions”) are preferred in this regard.Further, CA/TEC-Compositions in general preserve a higher lipase contentand usually possess a lower water content relative to other pancreatinmicropellets where other plasticizers are used. Furthermore,CA/TEC-Compositions exhibit a favorable dissolution profile which iscomparable to the presently marketed pancreatin containing medicaments,e.g. to medicaments available under the trade name Creon™.

In other embodiments of the invention, a pharmaceutical pack or kit isprovided comprising one or more containers filled with the pancreatinmicropellets described herein. Associated with such container(s) can bevarious written materials such as instructions for use, or a notice inthe form prescribed by a governmental agency regulating the manufacture,use or sale of pharmaceuticals products, which notice reflects approvalby the agency of manufacture, use, or sale for human or veterinaryadministration.

EXAMPLES

The following examples are meant to be illustrative and not to limit thepresent disclosure. Other suitable modifications and adaptations are ofthe variety normally encountered by those skilled in the art and arefully within the spirit and scope of the present disclosure.

A. Preparation of Pancreatin Micropellet Cores and PancreatinMicropellets 1. Preparation of Uncoated Pancreatin Micropellet Cores

15.9 kg of pancreatin was mixed with 3.975 kg of polyethylene glycol4000 in a commercially available high shear mixer and thoroughlymoistened with 3.975 kg of 2-propanol. The resulting mixture wasextruded by means of a commercially available extruding press which wasequipped with a piercing die having 0.8 mm internal diameter bores and acutting device arranged downstream. The temperature was less than 50° C.while pressing. The extruded mass was cut into extrudate fragments ofapproximately 5 mm length by means of the cutting device.

The resulting 14.64 kg of the extrudate fragments were transferred infour portions of roughly equal size to a commercially available roundingapparatus and rounded to give approximately elliptically orapproximately spherically shaped micropellet cores. An additional 135 gof 2-propanol was added while rounding.

After drying in a commercially available continuous vacuum dryer (VOtschtype) at a temperature in a range from between 35° C. and 50° C. for 12hours, the pancreatin micropellets were graded, first with a 3.15 mmsieve (sieving of oversize grain >3.15 mm) and then with a 0.7 mm sieve(sieving of undersize grain <0.7 mm) and afterwards with a 1.25 mm sieve(sieving of oversize grain >1.25 mm) to yield 11.98 kg of pancreatinmicropellet cores having a pancreatin content of 80% and a bulk densityof 0.67 g/ml.

2. Enteric Coating of Pancreatin Micropellet Cores

A coating solution was prepared by adding 1623.2 g of hydroxypropylmethylcellulose phthalate (HP 55), 90.2 g of triethyl citrate, 34.3 g ofcetyl alcohol and 38.9 g of dimethicone 1000 to 14030 g of acetone atroom temperature while stirring.

5025 g of pancreatin micropellet cores (prepared analogously to theprocess as described herein) were fed into a commercially availablefluid bed coater and were spray-coated at a spray rate of 97-101 kg/hand an air pressure of 1.7 bar with the coating solution as preparedabove until the desired film-thickness of the coating had been reached.The product temperature of the pancreatin micropellet cores wasmonitored and maintained in the range between about 37° C. and about 43°C. during coating. The resulting pancreatin micropellets were then driedin a commercially available vacuum dryer (Vötsch type) at a temperaturein a range between 35° C. and 50° C. for 12 hours. The dried pancreatinmicropellets were then graded, first with a 0.7 mm sieve (sieving ofundersize grain <0.7 mm) and then with a 1.6 mm sieve (sieving ofoversize grain >1.6 mm) to yield 6532 g of pancreatin micropelletshaving a pancreatin content of about 60% relative to the enteric-coatedpancreatin micropellets. The bulk density of the pancreatin micropelletswas about 0.69 g/ml.

Further pancreatin micropellets were prepared according to the proceduredescribed above and different coatings were applied in a manner similarto the coating process set forth above to yield additional pancreatinmicropellets. The compositions of the additional pancreatin micropelletsand certain process parameters from the coating processes are givenbelow in Table 1. Composition G can be produced according to processesas described in U.S. Pat. No. 5,378,462. Comparative composition H wasprepared according to a process as described above which has beenslightly modified (i.e. dibutylphthalate was used as a plasticizer inthe coating). All batches have been produced in laboratory scale exceptwhere otherwise indicated.

TABLE 1 Composition of (enteric-coated) pancreatin micropellets andapplicable process parameters Ingredients Composition mg/capsule A B C D1 2 Mi- Pancre- 150.00 150.00 150.00 150.00 150.00 150.00 cro- atinpellet PEG 37.50 37.50 37.50 37.50 37.50 37.50 Cores 4000 En- HP 5548.60 48.60 48.60 48.60 48.60 48.60 teric Dimeth- 1.25 1.25 1.25 1.251.25 1.25 Coat- icone ing TEC 0 0 3.0 4.10 5.00 0 (film) CA 0 0.40 0 0 01.00 Sum 237.40 237.75 240.35 241.45 242.4 238.35 Pro- Pellet 40° C. 40°C. 40° C. 40° C. 40° C. 40° C. cess temp. para- while me- coating tersIngredients Composition mg/capsule 3 4 5 6* 7 8 Mi- Pancre- 150.00150.00 150.00 150.00 150.00 150.00 cro- atin pellet PEG 37.50 37.5037.50 37.50 37.50 37.50 Cores 4000 En- HP 55 52.60 48.60 48.60 52.2552.25 52.25 teric Dimeth- 1.25 1.25 1.25 1.25 1.25 1.25 Coat- icone ingTEC 0 3.60 3.00 2.90 2.90 2.90 (film) CA 1.15 0.40 1.00 1.10 1.10 1.10Sum 242.50 241.35 241.35 245.00 245.00 245.00 Pro- Pellet 40° C. 40° C.40° C. 40° C. 30° C. 35° C. cess temp. para- while me- coating tersIngredients Composition mg/capsule 9 10 11 12 13 14 Mi- Pancre- 150.00150.00 150.00 150.00 150.00 150.00 cro- atin pellet PEG 37.50 37.5037.50 37.50 37.50 37.50 Cores 4000 En- HP 55 56.34 56.34 56.34 52.2552.25 56.34 teric Dimeth- 1.35 1.35 1.35 1.25 1.25 1.35 Coat- icone ingTEC 3.13 3.13 3.13 2.90 2.90 3.13 (film) CA 1.19 1.19 1.19 1.10 1.101.19 Sum 249.51 249.51 249.51 245.00 245.00 249.51 Pro- Pellet 37° C.40° C. 43° C. 49° C. 40° C. 46° C. cess temp. para- while me- coatingters Composition Ingredients mg/capsule 15 E F G H MicropelletPancreatin 128.06 150.00 150.00 150.00 150.00 PEG 4000 32.01 37.50 37.5037.50 37.50 Cores Light 0 0 0 3.75 0 mineral oil Enteric HP 55 48.1048.60 48.60 48.60 48.60 Coating Dimethi- 1.15 1.25 1.25 1.25 1.25 (film)cone TEC 2.67 1.00 2.00 0 0 CA 1.01 0 0 0 0 DBP 0 0 0 4.10 4.10 Light 00 0 3.30 0 mineral oil Sum 213.00 238.35 239.35 248.50 241.50 ProcessPellet n.a. 40° C. 40° C. 40° C. 40° C. parameters temp. while coatingPEG = polyethylene glycol; TEC = triethyl citrate; CA = cetyl alcohol;HP 55 = hydroxypropyl methylcellulose phthalate; temp. = temperature;DBP = dibutyl phthalate; * = production scale; n.a.: data not available.

Composition G is a currently available high-quality pharmaceuticalcomposition comprising pancreatin and light mineral oil.

Compositions No. 6, 10, 13, 14 and 15 are examples of CA/TECcompositions.

Composition No. 3 is an example of a composition comprising cetylalcohol as the plasticizer.

B. Determination of the Gastric Acid Resistance of Enteric-CoatedPancreatin Micropellets at pH 1 and pH 5

The gastric acid resistances of the pancreatin micropellet s (see Table1 hereabove) were measured.

Resistance to gastric juice (pH 1) of the different pancreatinmicropellets from Table 1 was determined by immersing the pancrelipasemicropellets for 2 hours in 0.1 mol/l hydrochloric acid in adisintegration tester according to the European Pharmacopoeia (Ph.Eur.). Then the un-dissolved portion of the pellets was separated fromthe solution and their residual lipase activity was determined accordingto the lipase assay of Ph. Eur./The International PharmaceuticalFederation” (FIP), PO Box 84200; 2508 AE The Hague; The Netherlands. Theresults of these tests for gastric resistance of the enteric coating arepresented in Table 2 (“stability at pH 1”).

Further, a similar test at pH 5 was performed using the same conditionsas outlined above, with the exception that a phosphate buffer pH 5.0(2.0 g sodium chloride and 9.2 g sodium di-hydrogen phosphatemonohydrate per liter adjusted to pH 5.0) was used as a solvent insteadof 0.1 mol/l hydrochloric acid. The results of these tests for gastricresistance are also presented below in Table 2 (“stability at pH 5”).

The gastric acid resistances of the compositions from Table 1 (seeabove) are each given in Table 2 as percentages of the residuallipolytic activity after the incubation in relation to the actuallipolytic activity of the samples tested prior to the incubation(relative gastric acid resistance). The lipolytic activity is determinedaccording to the lipase assay described in the USP monograph“pancrelipase delayed-release capsules”. In principle, any standardizedand characterized pancreatin sample may be used as the lipase referencestandard. For example, a predetermined lipolytic activity standard maybe obtained from the “International Pharmaceutical Federation” (FIP), POBox 84200; 2508 AE The Hague; The Netherlands. For the purposes of thepresent invention, an internal pancreatin standard was used which isavailable on request from Solvay Pharmaceuticals GmbH,Hans-Boeckler-Allee 20, 30173 Hannover, Germany.

TABLE 2 Relative gastric acid resistances (stabilities) of thepancreatin micropellets at pH 1 and pH 5 Stability at pH 5 Stability atpH 1 Composition [%] [%] A 15.3 15.9 B 63.2 53.8 C 71.6 84.2 D 52.0 93.61 87.0 96.0 2 76.4 92.6 3 92.1 94.5 4 85.3 93.7 5 92.0 93.0 6 94.9 99.47 67.4 89.8 8 80.5 95.2 9 83.8 90.8 10 97.9 99.6 11 89.0 93.5 12 83.794.8 13 100.2 102.7 14 93.6 98.7 E 48.6 65.0 F 36.5 75.0 G 98.6 100.6

Preferred pancreatin micropellets have a gastric acid resistance(stability) at pH 1 of at least 75%, in particular of at least 85%,preferably of at least 90%, more preferred of at least 95%, relative toa predetermined pancreatin lipolytic activity standard.

Other preferred pancreatin micropellets as disclosed herein have agastric acid resistance at pH 5 of at least 75%, in particular of atleast 85%, preferably of at least 90%, more preferred of at least 95%,relative to a predetermined pancreatin lipolytic activity standard.

Pancreatin micropellets which are most preferred have a gastric acidresistance at pH 1 of at least 90% and an additional gastric acidresistance at pH 5 of at least 90%, relative to a predeterminedpancreatin lipolytic activity standard.

C. Determination of the Dissolution Profile of Enteric Coated PancreatinMicropellets

The dissolution profile of different enteric coated pancreatinmicropellets from Table 1 (see above) was determined according to a testprocedure as described in the United States Pharmacopoeia (USP)monograph “pancrelipase delayed-release capsules” with increased gastricresistance phase which is hereby incorporated by reference.

The determination of the resistance to gastric fluid was performed usinggastric juice without enzymes according to USP under standardizedconditions (37° C., 100 rpm) for 2 hours in the dissolution apparatus(basket apparatus USP). Then the un-dissolved portion of the entericcoated pancreatin micropellets was separated from the solution andtransferred into the paddle apparatus according to USP, filled withphosphate buffer solution at pH 6.0 to determine the dissolution ofenzymes. The enteric coated pancreatin micropellets were agitated in adissolution tester under standardized conditions for usually 90 minutes(see exact timepoints in Table 3 below) at 37° C. and 50 rpm.

The lipase activity was determined after selected time points (see Table3) according to the lipase assay described in the USP monograph“pancrelipase delayed-release capsules”.

The results of the dissolution profile test are presented as “% residuallipase activity of actual lipase activity” below (see Table 3).

TABLE 3 Dissolution profiles of the enteric coated pancreatinmicropellets in phosphate buffer % lipase activity of initial actualactivity for pancreatin Time points micropellet composition No. [min.] GH 14 5 0.0 4 NA 10 0.0 6.25 15.37 15 11.9 23.15 34.38 20 48.0 48.15 NA25 62.3 62.9 NA 30 73.5 69.6 73.86 45 77.1 77.15 84.45 60 79.9 78.3581.25 75 78.4 76.7 80.40 90 78.2 75.25 NA

For the dissolution profile test results as provided in Table 3, acomparison of the compositions G, H and 14 was performed. The comparisonwas based on the “Guidance for Industry”, SUPAC-MR, Modified ReleaseSolid Oral Dosage Forms (September 1997) by calculating the similarityfactor (f2). The 2 acceptance limits for determining similarity of twocompared curves were (i) a factor (f2)>50 and (ii) the average deviationat any dissolution sampling point should not be greater than 15%.

In vitro dissolution profile comparisons can be made using a modelindependent approach using similarity factor. Dissolution profiles maybe compared using the following equation that defines a similarityfactor (f₂):

f ₂=50 log{[1+1/nΣ ^(n) _(t=1)(R _(t) −T _(t))²]^(−0.5)*100}

where log=logarithm to base 10, n=number of sampling time points,Σ=summation over all time points, R_(t)=dissolution at time point t ofthe reference (unchanged drug product, i.e. prechange batch),T_(t)=dissolution at time point t of the test (changed drug product,i.e., post-change batch).

When applying the above-stated acceptance limits for determiningsimilarity (f2=71.8) it was found that the dissolution profile ofpancreatin micropellet composition “H” (see Table 1) could be consideredto be similar to the dissolution profile of the reference pancreatinmicropellet composition “G” (see Table 1).

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference there individually and specificallyindicated to be incorporated by reference were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar references inthe context of this disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., such as, preferred, preferably) provided herein, isintended merely to further illustrate the content of the disclosure anddoes not pose a limitation on the scope of the claims. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the invention.

Alternative embodiments of the claimed invention are described herein,including the best mode known to the inventors for carrying out theclaimed invention. Of these, variations of the disclosed embodimentswill become apparent to those of ordinary skill in the art upon readingthe foregoing disclosure. The inventors expect skilled artisans toemploy such variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than as specifically describedherein.

Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

The use of individual numerical values are stated as approximations asthough the values were preceded by the word “about” or “approximately”unless clearly indicated otherwise by context. Similarly, the numericalvalues in the various ranges specified in this application, unlessexpressly indicated otherwise, are stated as approximations as thoughthe minimum and maximum values within the stated ranges were bothpreceded by the word “about” or “approximately.” In this manner,variations above and below the stated ranges can be used to achievesubstantially the same results as values within the ranges. As usedherein, the terms “about” and “approximately” when referring to anumerical value shall have their plain and ordinary meanings to a personof ordinary skill in the art to which the claimed subject matter is mostclosely related or the art relevant to the range or element at issue.The amount of broadening from the strict numerical boundary depends uponmany factors. For example, some of the factors which may be consideredinclude the criticality of the element and/or the effect a given amountof variation will have on the performance of the claimed subject matter,as well as other considerations known to those of skill in the art. Asused herein, the use of differing amounts of significant digits fordifferent numerical values is not meant to limit how the use of thewords “about” or “approximately” will serve to broaden a particularnumerical value. Thus, as a general matter, “about” or “approximately”broaden the numerical value. Also, the disclosure of ranges is intendedas a continuous range including every value between the minimum andmaximum values plus the broadening of the range afforded by the use ofthe term “about” or “approximately”. Thus, recitation of ranges ofvalues herein are merely intended to serve as a shorthand method ofreferring individually to each separate value falling within the range,unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein.

We claim:
 1. A process for the manufacture of pancreatin micropelletcores, comprising the steps of: a. preparing an extrudable mixturecomprising: i. about 10% to about 95% pancreatin; ii. about 5% to about90% of at least one pharmaceutically acceptable binding agent; iii. 0%to about 10% of at least one pharmaceutically acceptable excipient; andiv. one or more enzyme-friendly organic solvents in an amount sufficientto form an extrudable mixture; wherein the percentages of components areweight to weight of the pancreatin micropellet cores; b. creatingpancreatin micropellet cores from the extrudable mixture; c. forming thepancreatin micropellet cores into approximately spherical orapproximately ellipsoidal shape in the presence of additionalenzyme-friendly organic solvent; and d. removing the one or moreenzyme-friendly organic solvents from the pancreatin micropellet coressuch that the pancreatin micropellet cores are substantially free of theone or more enzyme-friendly organic solvents; wherein the pancreatinmicropellet cores are substantially free of synthetic oils.
 2. Theprocess of claim 1 wherein the pancreatin is present between about 70%and about 90% weight to weight of the pancreatin micropellet cores. 3.The process of claim 1 wherein the binding agent is present betweenabout 10% and about 30% weight to weight of the pancreatin micropelletcores.
 4. The process of claim 1 wherein the pharmaceutically acceptableexcipient is present between about 0% and about 5% weight to weight ofthe pancreatin micropellet cores.
 5. The process of claim 1 wherein thebinding agent is selected from the group consisting of: polyethyleneglycol 1500, polyethylene glycol 2000, polyethylene glycol 3000,polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol8000, polyethylene glycol 10000, hydroxypropyl methylcellulose,polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen andmixtures of said organic polymers.
 6. The process of claim 1 wherein thebinding agent is polyethylene glycol
 4000. 7. The process of claim 1wherein the at least one pharmaceutically acceptable excipient isselected from the group consisting of: magnesium stearate, calciumstearate, stearic acid, talcum, starch, calcium phosphate, corn starch,dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose,kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calciumcarbonate, sorbitol, silicic acid, alginic acid, amylose, calciumalginate, calcium carbonate, formaldehyde gelatin, pectic carbonate,sago starch, sodium bicarbonate and glycerol.
 8. The process of claim 1wherein the one or more enzyme-friendly organic solvents are presentbetween about 15% and about 35% by weight relative to the amount ofpancreatin.
 9. The process of claim 1 wherein the one or moreenzyme-friendly organic solvents are present in an amount of less thenabout 5% weight to weight of the pancreatin micropellet cores after theone or more enzyme-friendly organic solvents have been removed from thepancreatin micropellet cores.
 10. The process of claim 1 wherein the oneor more enzyme-friendly organic solvents is selected from the groupconsisting of: acetone, chloroform, dichloromethane, methanol, ethanol,1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of saidsolvents.
 11. The process of claim 1 wherein the one or moreenzyme-friendly organic solvents is 2-propanol.
 12. The process of claim1 wherein removing of the one or more enzyme-friendly organic solventsfrom the pancreatin micropellet cores is by drying at a temperaturebetween about 30° C. and about 75° C.
 13. The process of claim 1 whereincreating the pancreatin micropellet cores is by extrusion.
 14. Theprocess of claim 1 wherein forming of the pancreatin micropellet coresis performed in a rounding apparatus.
 15. A process for the manufactureof pancreatin micropellets, comprising the steps of: aa. providingpancreatin micropellet cores wherein the pancreatin micropellet coresare substantially free of synthetic oils; bb. providing anenteric-coating solution comprising i. one or more film-forming agents;ii. a plasticizer in an amount greater than about 1.5% by weightrelative to the one or more film-forming agents film-forming agents; andiii. optionally, at least one anti-sticking agent, and iv. one or moreenzyme-friendly organic solvent(s); cc. coating the pancreatinmicropellet cores with the enteric-coating solution wherein thetemperature of the pancreatin micropellet cores during coating is keptat a temperature suitable for applying the enteric-coating solution; anddd. drying the coated pancreatin micropellet cores.
 16. The process ofclaim 15 wherein the enteric coating is between about 20% and about 30%by weight of the pancreatin micropellets.
 17. The process of claim 15wherein the one or more film-forming agents is selected from the groupconsisting of: agar, carbomer polymers, carboxymethyl cellulose,carboxymethylethyl cellulose, carrageen, cellulose acetate phthalate,cellulose acetate succinate, cellulose acetate trimelliate, chitin, cornprotein extract, ethyl cellulose, gum arabic, hydroxypropyl cellulose,hydroxypropylmethyl acetate succinate, hydroxypropyl methylcelluloseacetate succinate, hydroxypropyl methylcellulose phthalate, methacrylicacid-ethyl methacrylate-copolymer, methyl cellulose, pectin, polyvinylacetate phthalate, polivinyl alcohol, shellac, sodium alginate, starchacetate phthalate, styrene/maleic acid copolymer and mixtures of saidfilm-forming polymers.
 18. The process of claim 15 wherein theplasticizer is selected from the group consisting of: saturated linearmonohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol,tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol,heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol,behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol,melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acidesters of glycerol, glycerol, polyethylene glycol, propyleneglycol,sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any ofsaid plasticizers.
 19. The process of claim 15 wherein the plasticizeris cetyl alcohol.
 20. The process of claim 15 wherein the plasticizer istriethyl citrate present in an amount of between about 5% and about 20%by weight relative to the film-forming agent.
 21. The process of claim15 wherein the plasticizer is comprised of cetyl alcohol and triethylcitrate which are collectively present in an amount greater than about3% by weight relative to the film-forming agent.
 22. The process ofclaim 15 wherein the plasticizer is comprised of cetyl alcohol andtriethyl citrate which are collectively present in an amount betweenabout 4% and about 20% by weight relative to the film-forming agent. 23.The process of claim 22 wherein the ratio of cetyl alcohol to triethylcitrate is between about 0.05:1 and about 1:1 by weight.
 24. The processof claim 15 wherein the anti-sticking agent is selected from the groupconsisting of: dimethicone and castor oil.
 25. The process of claim 15wherein the anti-sticking agent is present in an amount between about1.5% and about 3% by weight relative to the film-forming agent.
 26. Theprocess of claim 15 wherein the one or more enzyme-friendly organicsolvents is selected from the group consisting of: acetone, chloroform,dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol,tert-butanol and mixtures of said solvents.
 27. A method of treating amedical condition in a mammalian subject, comprising the steps of: a.providing pancreatin micropellet cores manufactured according to theprocess of claim 1 in a dosage form suitable for oral administration;and b. orally administering the dosage form to the subject to providepancreatin in an amount sufficient to treat the medical condition;wherein the medical condition is selected from the group consisting of:pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis,diabetes type I and diabetes type II.
 28. A method of treating a medicalcondition in a mammalian subject, comprising the steps of: a. providingpancreatin micropellets manufactured according to the process of claim15 in a dosage form suitable for oral administration; and b. orallyadministering the dosage form to the subject to provide pancreatin in anamount sufficient to treat the medical condition; wherein the medicalcondition is selected from the group consisting of: pancreatic exocrineinsufficiency, pancreatitis, cystic fibrosis, diabetes type I anddiabetes type II.
 29. A pharmaceutical composition, comprising a. apharmacologically effective amount of pancreatin wherein said pancreatinis in the form of pancreatin micropellet cores manufactured according tothe process of claim 1; and b. a dosage form suitable for oraladministration containing said pharmacologically effective amount ofpancreatin.
 30. A pharmaceutical composition, comprising a. apharmacologically effective amount of pancreatin wherein said pancreatinis in the form of pancreatin micropellets manufactured according to theprocess of claim 15; and b. a dosage form suitable for oraladministration containing said pharmacologically effective amount ofpancreatin.
 31. A pharmaceutical composition, prepared by a processcomprising the steps of: a. preparing an extrudable mixture comprising:i. about 10% to about 95% pancreatin; ii. about 5% to about 90% of atleast one pharmaceutically acceptable binding agent; iii. 0% to about10% of at least one pharmaceutically acceptable excipient; and iv. oneor more enzyme-friendly organic solvents in an amount sufficient to forman extrudable mixture; wherein the percentages of components are weightto weight of the pancreatin micropellet cores; b. creating pancreatinmicropellet cores from the extrudable mixture; c. forming the pancreatinmicropellet cores into approximately spherical or approximatelyellipsoidal shape in the presence of additional enzyme-friendly organicsolvent; d. removing the one or more enzyme-friendly organic solventsfrom the pancreatin micropellet cores such that the pancreatinmicropellet cores are substantially free of the one or moreenzyme-friendly organic solvents; wherein the pancreatin micropelletcores are substantially free of synthetic oils; e. coating thepancreatin micropellet cores with an enteric-coating solution whereinthe temperature of the pancreatin micropellet cores during coating is iskept at a temperature suitable to apply the enteric-coating solution; f.drying the coated pancreatin micropellet cores; and g. placing thecoated pancreatin micropellet cores in a dosage form suitable for oraladministration.
 32. The process of claim 31 wherein the pancreatin ispresent between about 70% and about 90% weight to weight of thepancreatin micropellet cores.
 33. The process of claim 31 wherein thebinding agent is present between about 10% and about 30% weight toweight of the pancreatin micropellet cores.
 34. The process of claim 31wherein the binding agent is selected from the group consisting of:polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethyleneglycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose,polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen andmixtures of said organic polymers.
 35. The process of claim 31 whereinthe binding agent is polyethylene glycol
 4000. 36. The process of claim31 wherein the at least one pharmaceutically acceptable excipient isselected from the group consisting of: magnesium stearate, calciumstearate, stearic acid, talcum, starch, calcium phosphate, corn starch,dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose,kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calciumcarbonate, sorbitol, silicic acid, alginic acid, amylose, calciumalginate, calcium carbonate, formaldehyde gelatin, pectic carbonate,sago starch, sodium bicarbonate and glycerol.
 37. The process of claim31 wherein the one or more enzyme-friendly organic solvents are presentbetween about 15% and about 35% by weight relative to the amount ofpancreatin.
 38. The process of claim 31 wherein the one or moreenzyme-friendly organic solvents is selected from the group consistingof: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol,2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 39.The process of claim 31 wherein the one or more enzyme-friendly organicsolvents is 2-propanol.
 40. The process of claim 31 wherein removing theone or more enzyme-friendly organic solvents from the pancreatinmicropellet cores is by drying at a temperature between about 30° C. andabout 75° C.
 41. A pharmaceutical composition, prepared by a processcomprising the steps of: a. providing pancreatin micropellet coreswherein the pancreatin micropellet cores are substantially free ofsynthetic oils; b. providing an enteric-coating solution comprising i.at least one film-forming agent ii. a plasticizer in an amount ofgreater than about 1.5% by weight relative to the one or morefilm-forming agents film-forming agents; and iii. optionally at leastone anti-sticking agent in one or more enzyme-friendly organic solvent;c. coating the pancreatin micropellet cores with the enteric-coatingsolution wherein the temperature of the pancreatin micropellet coresduring coating is kept at a temperature suitable to apply theenteric-coating solution ; and d. drying the coated pancreatinmicropellet cores; and e. placing the coated pancreatin micropelletcores in a dosage form suitable for oral administration.
 42. Thecomposition of claim 41 wherein the enteric coating is between about 20%and about 30% by weight of the pancreatin micropellets.
 43. Thecomposition of claim 41 wherein the one or more film-forming agents isselected from the group consisting of: agar, carbomer polymers,carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen,cellulose acetate phthalate, cellulose acetate succinate, celluloseacetate trimelliate, chitin, corn protein extract, ethyl cellulose, gumarabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methacrylic acid-ethylmethacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetatephthalate, polivinyl alcohol, shellac, sodium alginate, starch acetatephthalate, styrene/maleic acid copolymer and mixtures of saidfilm-forming polymers.
 44. The composition of claim 41 wherein theplasticizer is selected from the group consisting of: saturated linearmonohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol,tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol,heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol,behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol,melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acidesters of glycerol, glycerol, polyethylene glycol, propyleneglycol,sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any ofsaid plasticizers.
 45. The composition of claim 41 wherein theplasticizer is cetyl alcohol.
 46. The composition of claim 41 whereinthe plasticizer is triethyl citrate present in an amount of betweenabout 5% and about 20% by weight relative to the film-forming agent. 47.The composition of claim 41 wherein the plasticizer is a mixture ofcetyl alcohol and triethyl citrate which are collectively present in anamount of greater than about 3% by weight relative to the film-formingagent.
 48. The composition of claim 47 wherein the ratio of cetylalcohol to triethyl citrate is between about 0.05:1 and about 1:1 byweight.
 49. The composition of claim 41 wherein the anti-sticking agentis selected from the group consisting of: dimethicone and castor oil.50. The composition of claim 41 wherein the anti-sticking agent ispresent in an amount between about 1.5% and about 3% by weight relativeto the film-forming agent.
 51. The composition of claim 41 wherein theone or more enzyme-friendly organic solvents is selected from the groupconsisting of: acetone, chloroform, dichloro-methane, methanol, ethanol,1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of saidsolvents.
 52. A pharmaceutical composition comprising: pancreatinmicropellets wherein the pancreatin micropellets are substantially freeof synthetic oils and wherein said pancreatin micropellets have agastric acid resistance of about 75% or more at about a pH
 1. 53. Apharmaceutical composition comprising: pancreatin micropellets whereinthe pancreatin micropellets are substantially free of synthetic oils andwherein said pancreatin micropellets have a gastric acid resistance ofabout 75% or more at about a pH
 5. 54. A pharmaceutical compositioncomprising: a. pancreatin micropellet cores wherein the pancreatinmicropellet cores are substantially free of synthetic oils; b. at leastone film-forming agent; c. a plasticizer in an amount greater than about1.5% by weight relative to the one or more film-forming agents; and d.optionally at least one anti-sticking agent in one or moreenzyme-friendly organic solvent.